Publications by authors named "Jean-Baptiste Lattouf"

98 Publications

Overexpression of Nrf2 in Renal Proximal Tubular Cells Stimulates Sodium-Glucose Co-Transporter 2 Expression and Exacerbates Dysglycemia and Kidney Injury in Diabetic Mice.

Diabetes 2021 Apr 5. Epub 2021 Apr 5.

Centre de recherche, Centre hospitalier de l'Université de Montréal (CRCHUM) and Département de médecine, Université de Montréal, 900 Saint Denis Street, Montréal, QC H2X 0A9, Canada

We investigated the impact of nuclear factor erythroid 2-related factor 2 (Nrf2) overexpression in renal proximal tubular cells (RPTCs) on blood glucose, kidney injury and sodium-glucose co-transporter 2 (Sglt2) expression in diabetic Akita transgenic (Tg) mice. Immortalized human RPTCs (HK2) stably transfected with plasmid containing the promoter, human kidneys from patients with diabetes were also studied. Nrf2 overexpression was associated with increased blood glucose, glomerular filtration rate, urinary albumin-creatinine ratio, tubulointerstitial fibrosis and Sglt2 expression in Akita Tg mice compared to their Akita littermates. , oltipraz or transfection of cDNA stimulated expression and promoter activity in HK2, and these effects were inhibited by trigonelline or small interfering RNA. The deletion of the in the promoter abolished the stimulatory effect of oltipraz on promoter activity. NRF2 binding to the of the promoter was confirmed by gel mobility shift assay and chromatin immunoprecipitation assays. Kidneys from patients with diabetes exhibited higher levels of NRF2 and SGLT2 in the RPTCs than kidneys from patients without diabetes. These results suggest a link by which NRF2 mediates hyperglycemia-stimulation of SGLT2 expression and exacerbates blood glucose and kidney injury in diabetes.
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http://dx.doi.org/10.2337/db20-1126DOI Listing
April 2021

Lymph node dissection during radical nephrectomy: A Canadian multi-institutional analysis.

Urol Oncol 2021 Mar 27. Epub 2021 Mar 27.

The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

Objectives: To determine the association between lymph node dissection (LND) at the time of radical nephrectomy and survival in a large, multi-institutional cohort using a propensity score matching design.

Subjects And Methods: The Canadian Kidney Cancer information system was used to identify patients undergoing radical nephrectomy for nonmetastatic renal cell carcinoma. Associations between LND with overall survival , recurrence free survival and cancer specific survival were determined using various propensity score techniques in the overall cohort and in patients with varying probabilities of pN1. Cox models were used to determine association of lymph node removed with outcomes.

Results: Of the 2,699 eligible patients, 812 (30%) underwent LND. Of the LND patients, 88 (10.8%) had nodal metastases. There was no association between LND and improved overall survival, recurrence free survival or cancer specific survival using various propensity score techniques (stratification by propensity score quintile, matched pairs, inverse treatment probability weighting and adjusted for propensity score quintile). There was no association between LND and a therapeutic benefit in patients with increased threshold probabilities of nodal metastases. Increased number of lymph nodes removed was not associated with improved survival outcomes.

Conclusions: LND at the time of radical nephrectomy for renal cell carcinoma is not associated with improved outcomes. There was no benefit in patients at high risk for nodal metastases, and the number of nodes removed did not correlate with survival. Further studies are needed to determine which high risk patients may benefit from LND.
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http://dx.doi.org/10.1016/j.urolonc.2021.02.025DOI Listing
March 2021

Niraparib with androgen receptor-axis-targeted therapy in patients with metastatic castration-resistant prostate cancer: safety and pharmacokinetic results from a phase 1b study (BEDIVERE).

Cancer Chemother Pharmacol 2021 Mar 22. Epub 2021 Mar 22.

Norton Cancer Institute, Louisville, KY, USA.

Purpose: To assess the safety and pharmacokinetics and determine the recommended phase 2 dose (RP2D) of niraparib with apalutamide or abiraterone acetate plus prednisone (AAP) in patients with metastatic castration-resistant prostate cancer (mCRPC).

Methods: BEDIVERE was a multicenter, open-label, phase 1b study of niraparib 200 or 300 mg/day with apalutamide 240 mg or AAP (abiraterone acetate 1000 mg; prednisone 10 mg). Patients with mCRPC were previously treated with ≥ 2 lines of systemic therapy, including ≥ 1 androgen receptor-axis-targeted therapy for prostate cancer.

Results: Thirty-three patients were enrolled (niraparib-apalutamide, 6; niraparib-AAP, 27). No dose-limiting toxicities (DLTs) were reported when combinations included niraparib 200 mg; five patients receiving niraparib 300 mg experienced DLTs [niraparib-apalutamide, 2/3 patients (66.7%); niraparib-AAP, 3/8 patients (37.5%)]. Although data are limited, niraparib exposures were lower when given with apalutamide compared with historical niraparib monotherapy exposures in patients with solid tumors. Because of the higher incidence of DLTs, the niraparib-apalutamide combination and niraparib 300 mg combination with AAP were not further evaluated. Niraparib 200 mg was selected as the RP2D with AAP. Of 19 patients receiving niraparib 200 mg with AAP, 12 (63.2%) had grade 3/4 treatment-emergent adverse events, the most common being thrombocytopenia (26.3%) and hypertension (21.1%). Five patients (26.3%) had adverse events leading to treatment discontinuation.

Conclusions: These results support the choice of niraparib 200 mg as the RP2D with AAP. The niraparib-AAP combination was tolerable in patients with mCRPC, with no new safety signals. An ongoing phase 3 study is further assessing this combination in patients with mCRPC.

Trial Registration No: NCT02924766 (ClinicalTrials.gov).
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http://dx.doi.org/10.1007/s00280-021-04249-7DOI Listing
March 2021

Comparing Perspectives of Canadian Men Diagnosed With Prostate Cancer and Health Care Professionals About Active Surveillance.

J Patient Exp 2020 Dec 11;7(6):1122-1129. Epub 2020 Jun 11.

Institut du cancer de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal, Quebec, Canada.

Active surveillance (AS) has gained acceptance as a primary management approach for patients diagnosed with low-risk prostate cancer (PC). In this qualitative study, we compared perspectives between patients and health care professionals (HCP) to identify what may contribute to patient-provider discordance, influence patient decision-making, and interfere with the uptake of AS. We performed a systematic comparison of perspectives about AS reported from focus groups with men eligible for AS (7 groups, N = 52) and HCP (5 groups, N = 48) who engaged in conversations about AS with patient. We used conventional content analysis to scrutinize separately focus group transcripts and reached a consensus on similar or divergent viewpoints between them. Patients and clinicians agreed that AS was appropriate for low grade PC and understood the low-risk nature of the disease. They shared the perspective that disease status was a critical factor to pursue or discontinue AS. However, men expressed a greater emphasis on quality of life in their decisions related to AS. Patients and clinicians differed in their perspectives on the clarity, availability, and volume of information needed and offered; clinicians acknowledged variations between HCP when presenting AS, while patients were often compelled to seek additional information beyond what was provided by physicians and experienced difficulty in finding or interpreting information applicable to their situation. A greater understanding of discordant perspectives about AS between patients and HCP can help improve patient engagement and education, inform development of knowledge-based tools or aids for decision-making, and identify areas that require standardization across the clinical practice.
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http://dx.doi.org/10.1177/2374373520932735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786672PMC
December 2020

Canadian Urological Association best practice report: Diagnosis and management of sporadic angiomyolipomas.

Can Urol Assoc J 2020 Nov;14(11):E527-E536

Division of Urology, Department of Surgery, Trillium Health Partners, Mississauga, ON, Canada.

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http://dx.doi.org/10.5489/cuaj.6942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673831PMC
November 2020

Prognostic impact of paraneoplastic syndromes on patients with non-metastatic renal cell carcinoma undergoing surgery: Results from Canadian Kidney Cancer information system.

Can Urol Assoc J 2021 Apr;15(4):132-137

Department of Surgery, University of Manitoba, Winnipeg, MB, Canada.

Introduction: The impact of paraneoplastic syndromes (PNS) on survival in patients with renal cell carcinoma (RCC) is uncertain. This study was conducted to analyze the association of PNS with recurrence and survival of patients with non-metastatic RCC undergoing nephrectomy.

Methods: The Canadian Kidney Cancer information system is a multi-institutional cohort of patients started in January 2011. Patients with nephrectomy for non-metastatic RCC were identified. PNS included anemia, polycythemia, hypercalcemia, and weight loss. Associations between PNS and recurrence or death were assessed using Kaplan-Meier curves and multivariable analysis.

Results: Of 4337 patients, 1314 (30.3%) had evidence of one or more PNS. Patients with PNS were older, had higher comorbidity, and had more advanced clinical and pathological tumor characteristics as compared to patients without PNS (all p<0.05). Kaplan-Meier five-year estimated recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) were significantly worse in patients with PNS (63.7%, 84.3%, and 79.6%, respectively, for patients with PNS vs. 73.9%, 90.8%, and 90.1%, respectively, for patients without PNS, all p<0.005). On univariable analysis, presence of PNS increased risk of recurrence (hazard ratio [HR] 1.67, 95% confidence interval [CI] 1.48-1.90, p<0.0001) and cancer-related death (HR 1.85, 95% CI 1.34-2.54, p=0.0002). Adjusting for known prognostic factors, PNS was not associated with recurrence or survival.

Conclusions: In non-metastatic RCC patients undergoing surgery, presence of PNS is associated with older age, higher Charlson comorbidity index score, advanced tumor stage, and aggressive tumor histology. Following surgery, baseline PNS is not strongly independently associated with recurrence or death.
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http://dx.doi.org/10.5489/cuaj.6833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021432PMC
April 2021

Impact of Time to Surgery and Surgical Delay on Oncologic Outcomes for Renal Cell Carcinoma.

J Urol 2021 Jan 2;205(1):78-85. Epub 2020 Jul 2.

Section of Urology, University of Manitoba, Winnipeg, Manitoba, Canada.

Purpose: The time between radiographic identification of a renal tumor and surgery can be concerning for patients and clinicians due to fears of tumor progression while awaiting treatment. This study aimed to evaluate the association between surgical wait time and oncologic outcomes for patients with renal cell carcinoma.

Materials And Methods: The Canadian Kidney Cancer Information System is a multi-institutional prospective cohort initiated in January 2011. Patients with clinical stage T1b or greater renal cell carcinoma diagnosed between January 2011 and December 2019 were included in this analysis. Outcomes of interest were pathological up staging, cancer recurrence, cancer specific survival and overall survival. Time to recurrence and death were estimated using Kaplan-Meier estimates and associations were determined using Cox proportional hazards models.

Results: A total of 1,769 patients satisfied the study criteria. Median wait times were 54 days (IQR 29-86) for the overall cohort and 81 days (IQR 49-127) for cT1b tumors (1,166 patients), 45 days (IQR 27-71) for cT2 tumors (672 cases) and 35 days (IQR 18-61) for cT3/4 tumors (563). Adjusting for comorbidity, tumor size, grade, histological subtype, margin status and pathological stage, there was no association between prolonged wait time and cancer recurrence or death.

Conclusions: In the context of current surgeon triaging practices surgical wait times up to 24 weeks were not associated with adverse oncologic outcomes after 2 years of followup.
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http://dx.doi.org/10.1097/JU.0000000000001230DOI Listing
January 2021

A Plea for Optimizing Selection in Current Adjuvant Immunotherapy Trials for High-risk Nonmetastatic Renal Cell Carcinoma According to Expected Cancer-specific Mortality.

Clin Genitourin Cancer 2020 08 5;18(4):314-321.e1. Epub 2019 Dec 5.

Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, QC, Canada; Division of Urology, University of Montreal Hospital Center, Montreal, QC, Canada.

Background: Tyrosine kinase inhibitor-based adjuvant therapy showed no survival benefits for patients with high-risk nonmetastatic renal cell carcinoma (nmRCC). Five randomized immune-oncology checkpoint inhibitor trials are ongoing. We assessed the effect of stage, grade, and histologic type on cancer-specific mortality (CSM) in candidates for 1 of the 4 North American ongoing immune-oncology checkpoint inhibitor trials of high-risk nmRCC.

Patients And Methods: From the Surveillance, Epidemiology, and End Results database (2001-2015), we identified patients who had undergone surgery for nmRCC and had met the inclusion criteria for the PROSPER RCC (nivolumab in treating patients with localized kidney cancer undergoing nephrectomy), CheckMate 914 (a study comparing the combination of nivolumab and ipilimumab versus placebo in participants with localized renal cell carcinoma), KEYNOTE-564 [safety and efficacy study of pembrolizumab (MK-3475) as monotherapy in the adjuvant treatment of renal cell carcinoma post nephrectomy], or IMmotion010 [a study of atezolizumab as adjuvant therapy in participants with renal cell carcinoma (RCC) at high risk of developing metastasis following nephrectomy] trials. Kaplan-Meier and multivariable Cox regression models were used to assess the 10-year CSM rates in the overall cohort according to stage, grade, and histologic characteristics, and in 4 generated random samples according to the eligible patients for each of the 4 trials.

Results: Of 116,750 patients who had undergone surgery for nmRCC, 18,559 (15.9%) had fulfilled the inclusion criteria for 1 of the 4 trials. The greatest proportion of higher stage and grade combinations and sarcomatoid histologic features would have qualified for IMmotion010, followed by KEYNOTE-564, CheckMate 914, and PROSPER RCC. Multivariable Cox regression models demonstrated the most unfavorable prognosis for stage N1 grade 3/4 (hazard ratio [HR], 11.5; P < .001), stage T4N0 grade 3/4 (HR, 9.8; P < .001), and sarcomatoid histologic features (HR, 5.5; P < .001). Among the 4 random samples, the difference in the qualifying criteria resulted in the greatest versus progressively lower CSM rates in the IMmotion010, KEYNOTE-564, CheckMate 914, and PROSPER RCC trials, respectively (P < .001).

Conclusions: Our findings indicate that participation in adjuvant immunotherapy trials should be predominantly encouraged for patients with high-grade stage T3, T4, and N1 and patients with any stage with sarcomatoid pathologic features.
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http://dx.doi.org/10.1016/j.clgc.2019.11.010DOI Listing
August 2020

Increased urinary excretion of hedgehog interacting protein (uHhip) in early diabetic kidney disease.

Transl Res 2020 03 18;217:1-10. Epub 2019 Nov 18.

Department of Medicine, Université de Montréal, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Quebec, Canada. Electronic address:

Glomerular endothelial cell (GEC) dysfunction occurs in diabetic kidney disease (DKD) and generally precedes albuminuria. We recently reported that hedgehog interacting protein (Hhip), highly expressed in GECs, contributes to DKD development in diabetic mice. Here, we hypothesized that urinary Hhip (uHhip) could identify early DKD; we tested uHhip in mice and humans with diabetes (DM). In both type 1 (Akita) and type 2 (db/db) DM mice, uHhip is elevated prior to the development of albuminuria, while non-DM controls excrete minimal amount of uHhip. In 87 type 2 DM patients and 39 healthy controls, the uHhip/creatinine (Cr) ratio provides a significant discrimination between non-DM and DM groups; 0 [0-69.5] in non-DM, 9.9 [1.7-39.5] in normoalbuminuric DM, 167.7 [95.7-558.7] in microalbuminuric DM, and 207.9 [0-957.2] in macroalbuminuric DM (median [IQR] ng/mmol, P < 0.0001). The log-uHhip/Cr is positively correlated with urine albumin/Cr ratio (UACR) (spearman correlation coefficient 0.47, P < 0.0001). The log-uHhip/Cr is also associated with eGFR, pulse pressure, and urinary cytokines (IL-1β, IL-6, IL-8, and TGFβ1) independent of UACR. By immunostaining, Hhip is localized in glomeruli and tubules, and is increased in human DM kidneys compared with non-DM kidneys. TGFβ1 shares the similar staining pattern as Hhip in human DM kidneys. Thus, uHhip appears to be a novel indicator of diabetic GEC injury and is elevated in early DKD before the development of microalbuminuria in mice and humans. Clinical value for detecting early DKD warrants further investigation.
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http://dx.doi.org/10.1016/j.trsl.2019.11.001DOI Listing
March 2020

Controversial issues in the management of patients with advanced prostate cancer: Results from a Canadian consensus forum.

Can Urol Assoc J 2020 Apr 5;14(4):E137-E149. Epub 2019 Nov 5.

BC Cancer Agency, University of British Columbia, Vancouver, BC, Canada.

Introduction: The management of advanced prostate cancer (PCa) continues to evolve with the emergence of new diagnostic and therapeutic strategies. As a result, there are multiple areas in this landscape with a lack of high-level evidence to guide practice. Consensus initiatives are an approach to establishing practice guidance in areas where evidence is unclear. We conducted a Canadian-based consensus forum to address key controversial areas in the management of advanced PCa.

Methods: As part of a modified Delphi process, a core scientific group of PCa physicians (n=8) identified controversial areas for discussion and developed an initial set of questions, which were then reviewed and finalized with a larger group of 29 multidisciplinary PCa specialists. The main areas of focus were non-metastatic castration-resistant prostate cancer (nmCRPC), metastatic castration-sensitive prostate cancer (mCSPC), metastatic castration-resistant prostate cancer (mCRPC), oligometastatic prostate cancer, genetic testing in prostate cancer, and imaging in advanced prostate cancer. The predetermined threshold for consensus was set at 74% (agreement from 20 of 27 participating physicians).

Results: Consensus participants included uro-oncologists (n=13), medical oncologists (n=10), and radiation oncologists (n=4). Of the 64 questions, consensus was reached in 30 questions (n=5 unanimously). Consensus was more common for questions related to biochemical recurrence, sequencing of therapies, and mCRPC.

Conclusions: A Canadian consensus forum in PCa identified areas of agreement in nearly 50% of questions discussed. Areas of variability may represent opportunities for further research, education, and sharing of best practices. These findings reinforce the value of multidisciplinary consensus initiatives to optimize patient care.
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http://dx.doi.org/10.5489/cuaj.6082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7124178PMC
April 2020

Contemporary Incidence and Mortality Rates in Patients With Testicular Germ Cell Tumors.

Clin Genitourin Cancer 2019 10 13;17(5):e1026-e1035. Epub 2019 Jun 13.

Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Quebec, Canada; Division of Urology, University of Montreal Hospital Center (CHUM), Montreal, Quebec, Canada.

Background: We comprehensively tested contemporary incidence and mortality rates in patients with germ cell tumor of the testis (GCTT).

Materials And Methods: Within the Surveillance, Epidemiology, and End Results database (2004-2015), statistical analyses included estimated annual percentage changes, multivariable logistic regression (MLR) models, Kaplan-Meier curves, and multivariable Cox regression (MCR) models.

Results: Of 13,114 GCTT patients, 7954 (60.6%) harbored seminoma germ cell tumors of the testis (SGCTT) and 5160 (39.4%) non-SGCTT (NSGCTT). Relative to SGCTT, NSGCTT patients harbored more advanced stage (for stage III 824 [16.0%] vs. 279 patients [3.5%]; P < .001). In MLR, higher rates of stage II/III affected those with never-married status (odds ratio [OR], 1.6; P < .001) and African American ethnicity (OR, 1.5; P = .005) for SGCTT and never-married (OR, 1.3; P = .002) and Hispanic ethnicity (OR, 1.3; P < .001) for NSGCTT. Significant differences in 5-year cancer-specific mortality (CSM) distinguished SGCTT (stage I: 0.4; stage II: 3.4; stage III: 11.4%; P < .001) from NSGCTT (stage I: 1.6; stage II: 2.5; stage III: 22.2%; P < .001). In MCR, unmarried status independently predicted higher CSM for SGCTT (hazard ratio [HR], 2.1; P = .007) and NSGCTT (HR, 1.9; P < .001).

Conclusion: Stage I and stage III NSGCTT survival is worse, than for SGCTT. Never-married, Hispanic, and African American individuals are at higher risk of more advanced stage and/or CSM in SGCTT and NSGCTT.
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http://dx.doi.org/10.1016/j.clgc.2019.06.003DOI Listing
October 2019

Outcomes and prognosticators of stage 4 renal cell carcinoma with pathological T4 primary lesion using a large, Canadian, multi-institutional database.

Can Urol Assoc J 2020 Feb 23;14(2):24-30. Epub 2019 Jul 23.

Section of Urology, University of Manitoba, Winnipeg, MB, Canada.

Introduction: The primary objective of this study was to evaluate outcomes and prognosticators in patients who underwent radical nephrectomy (RN) or cytoreductive nephrectomy (CN), depending on the clinical stage of disease preoperatively, with a pathological T4 (pT4) renal cell carcinoma (RCC) outcome. There is little data on the outcome of this specific subset of patients.

Methods: From 2009-2016, we identified patients in the Canadian Kidney Cancer information system (CKCis) who underwent RN or CN and were found to have pT4 RCC. Clinical, operative, and pathological variables were analyzed with univariable and multivariable Cox proportional hazard models to identify factors associated with overall survival (OS). Survival curves were created using Kaplan-Meier methods and compared using the log-rank test.

Results: A total of 82 patients were included in the study cohort. Median patient age was 62 years (interquartile range [IQR] 55, 70). Fifty (61%) patients had clear-cell histology and 14 (17%) had sarcomatoid characteristics. Median followup was 12 months (IQR 3, 24). At last followup, eight (10%) patients are alive with no evidence of disease, 27 (33%) are alive with disease, four (5%) were lost to followup, 36 (44%) died of disease, and seven (8%) died of other causes. Tumor histological subtype (clear-cell vs. non-clear-cell) (p=0.0032), larger tumor size (cm) (p=0.012), and Fuhrman grade (G4 vs. G2-G3) (p=0.045) were significantly associated with mortality in a multivariable Cox regression model.

Conclusions: For patients with pT4 RCC after RN or CN, survival is poor. Sarcomatoid features, non-clear-cell histology, and presence of systemic symptoms were associated with worse OS.
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http://dx.doi.org/10.5489/cuaj.5941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012283PMC
February 2020

Validation of the prognostic value of NF-κB p65 in prostate cancer: A retrospective study using a large multi-institutional cohort of the Canadian Prostate Cancer Biomarker Network.

PLoS Med 2019 07 2;16(7):e1002847. Epub 2019 Jul 2.

Centre de recherche du Centre hospitalier de l'Université de Montréal, Centre hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.

Background: The identification of patients with high-risk prostate cancer (PC) is a major challenge for clinicians, and the improvement of current prognostic parameters is an unmet clinical need. We and others have identified an association between the nuclear localization of NF-κB p65 and biochemical recurrence (BCR) in PC in small and/or single-centre cohorts of patients.

Methods And Findings: In this study, we accessed 2 different multi-centre tissue microarrays (TMAs) representing cohorts of patients (Test-TMA and Validation-TMA series) of the Canadian Prostate Cancer Biomarker Network (CPCBN) to validate the association between p65 nuclear frequency and PC outcomes. Immunohistochemical staining of p65 was performed on the Test-TMA and Validation-TMA series, which include PC tissues from patients treated by first-line radical prostatectomy (n = 250 and n = 1,262, respectively). Two independent observers evaluated the p65 nuclear frequency in digital images of cancer tissue and benign adjacent gland tissue. Kaplan-Meier curves coupled with a log-rank test and univariate and multivariate Cox regression models were used for statistical analyses of continuous values and dichotomized data (cutoff of 3%). Multivariate analysis of the Validation-TMA cohort showed that p65 nuclear frequency in cancer cells was an independent predictor of BCR using continuous (hazard ratio [HR] 1.02 [95% CI 1.00-1.03], p = 0.004) and dichotomized data (HR 1.33 [95% CI 1.09-1.62], p = 0.005). Using a cutoff of 3%, we found that this biomarker was also associated with the development of bone metastases (HR 1.82 [95% CI 1.05-3.16], p = 0.033) and PC-specific mortality (HR 2.63 [95% CI 1.30-5.31], p = 0.004), independent of clinical parameters. BCR-free survival, bone-metastasis-free survival, and PC-specific survival were shorter for patients with higher p65 nuclear frequency (p < 0.005). As the small cores on TMAs are a limitation of the study, a backward validation of whole PC tissue section will be necessary for the implementation of p65 nuclear frequency as a PC biomarker in the clinical workflow.

Conclusions: We report the first study using the pan-Canadian multi-centre cohorts of CPCBN and validate the association between increased frequency of nuclear p65 frequency and a risk of disease progression.
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http://dx.doi.org/10.1371/journal.pmed.1002847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605640PMC
July 2019

Contemporary Assessment of Survival Rates in Stage I Testicular Seminoma: A Population-Based Comparison Between Surveillance and Active Treatment After Orchiectomy.

Clin Genitourin Cancer 2019 08 30;17(4):e793-e801. Epub 2019 Apr 30.

Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Québec, Canada; Division of Urology, University of Montreal Hospital Center (CHUM), Montreal, Quebec, Canada.

Background: We tested contemporary surveillance and active treatment (AT) that included chemotherapy (CHT) and radiotherapy (RT) rates for stage I testicular seminoma patients, as well as cancer-specific mortality (CSM) and other-cause mortality (OCM) rates.

Patients And Methods: Within the Surveillance, Epidemiology, and End Results database (1988-2015) we identified 11,206 stage I testicular seminoma patients. Surveillance versus CHT versus RT use rates were investigated using estimated annual percentage change (EAPC) analyses. After propensity score (PS) matching, cumulative incidence plots and multivariable competing risks regression models (MCRRMs) tested for CSM and OCM.

Results: Of all 11,206 patients, 4434 (40%), 918 (8%), and 5854 (52%), respectively, underwent surveillance, CHT, or RT after initial orchiectomy. Surveillance (EAPC: 7.5%; P < .001) and CHT (EAPC: 13.5%; P < .001) rates increased over time, whereas RT rates decreased (EAPC: -3.8%; P < .001). After PS matching, in MCRRMs surveillance was an independent predictor of CSM, relative to AT (hazard ratio [HR], 2.59; P = .04). Conversely, surveillance versus AT did not affect OCM (HR, 1.52; P = .051). All other analyses that focused on CSM and OCM, namely surveillance versus RT, surveillance versus CHT, and RT versus CHT resulted in nonsignificant differences (all P > .5).

Conclusion: Surveillance and CHT use in stage I testicular seminoma rates increased, whereas RT rate decreased over time. A protective effect of AT defined as either RT or CHT was identified on CSM, relative to surveillance. This protective effect was not described for OCM. No differences in survival were recorded, when individual management strategies (surveillance vs. RT vs. CHT) were compared with each other.
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http://dx.doi.org/10.1016/j.clgc.2019.04.015DOI Listing
August 2019

Morphologic subtyping as a prognostic predictor for survival in papillary renal cell carcinoma: Type 1 vs. type 2.

Urol Oncol 2019 10 5;37(10):721-726. Epub 2019 Jun 5.

Department of Surgery, Division of Urology, Hamilton, Ontario. Electronic address:

Objective: To evaluate outcomes of surgically treated patients with clinically localized papillary renal cell carcinoma (RCC) and determine if papillary RCC subtype is associated with recurrence and survival.

Methods: This is a historical cohort study using the prospectively maintained Canadian Kidney Cancer Information System database between January 2011 and September 2018. All patients underwent partial or radical nephrectomy. Patient, tumor, treatment, and outcomes were compared between papillary RCC type 2 and type 1 cohorts.

Results: During the study period, 509 patients had clinically localized papillary RCC type 2 (n = 172) or type 1 (n = 337) histology. Sex, race, and comorbidities were similar between groups. Pathologic stage (pT3 or pT4), nuclear grade (3 or 4), and tumor diameter were higher in the type 2 papillary RCC cohort (P < 0.0001). A greater proportion of type 2 papillary RCC patients received radical nephrectomy (42.4% vs. 24.6%, P< 0.0001). More type 2 papillary RCC patients underwent lymph node dissection (19.6% vs. 5.5%, P< 0.0001) and had lymph node metastases removed during surgery (6.4% vs. 0.6%, P= 0.103). Overall, adjusting for age, grade, pathologic stage, positive nodes, and tumor size, type 2 papillary RCC had worse outcomes compared to type 1, as demonstrated by elevated all-cause mortality (hazard ratio = 7.7 [95% confidence interval: 2.0-28.9]), P=0.0027) and worse recurrence-free survival (hazard ratio = 8.2 [95% confidence interval: 3.6-19.0], P< 0.0001).

Conclusion: Patients with clinically localized type 2 papillary RCC present with higher risk disease and have worse prognosis compared to patients with clinically localized type 1 papillary RCC. To the best of our knowledge, this is the largest cohort study comparing papillary RCC subtypes.
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http://dx.doi.org/10.1016/j.urolonc.2019.05.009DOI Listing
October 2019

Failed immune responses across multiple pathologies share pan-tumor and circulating lymphocytic targets.

J Clin Invest 2019 03 26;129(6):2463-2479. Epub 2019 Mar 26.

University of Montreal Hospital Research Centre, Montreal, Quebec, Canada.

Rationale Tumor infiltrating lymphocytes are widely associated with positive outcomes, yet carry key indicators of a systemic failed immune response against unresolved cancer. Cancer immunotherapies can reverse their tolerance phenotypes, while preserving tumor-reactivity and neoantigen-specificity shared with circulating immune cells. Objectives We performed comprehensive transcriptomic analyses to identify gene signatures common to circulating and tumor infiltrating lymphocytes in the context of clear cell renal cell carcinoma. Modulated genes also associated with disease outcome were validated in other cancer types. Findings Using bioinformatics, we identified practical diagnostic markers and actionable targets of the failed immune response. On circulating lymphocytes, three genes, LEF1, FASLG, and MMP9, could efficiently stratify patients from healthy control donors. From their associations with resistance to cancer immunotherapies and microbial infections, we uncovered not only pan-cancer, but pan-pathology failed immune response profiles. A prominent lymphocytic matrix metallopeptidase cell migration pathway, is central to a panoply of diseases and tumor immunogenicity, correlates with multi-cancer recurrence, and identifies a feasible, non-invasive approach to pan-pathology diagnoses. Conclusions The non-invasive differently expressed genes we have identified warrant future investigation towards the development of their potential in precision diagnostics and precision pan-disease immunotherapeutics.
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http://dx.doi.org/10.1172/JCI125301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546483PMC
March 2019

The Terry Fox Research Institute Canadian Prostate Cancer Biomarker Network: an analysis of a pan-Canadian multi-center cohort for biomarker validation.

BMC Urol 2018 Sep 10;18(1):78. Epub 2018 Sep 10.

Institut du cancer de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal, 900, St-Denis St, room R10-464, Montréal, Québec, H2X 0A9, Canada.

Background: Refinement of parameters defining prostate cancer (PC) prognosis are urgently needed to identify patients with indolent versus aggressive disease. The Canadian Prostate Cancer Biomaker Network (CPCBN) consists of researchers from four Canadian provinces to create a validation cohort to address issues dealing with PC diagnosis and management.

Methods: A total of 1512 radical prostatectomy (RP) specimens from five different biorepositories affiliated with teaching hospitals were selected to constitute the cohort. Tumoral and adjacent benign tissues were arrayed on tissue microarrays (TMAs). A patient clinical database was developed and includes data on diagnosis, treatment and clinical outcome.

Results: Mean age at diagnosis of patients in the cohort was 61 years. Of these patients, 31% had a low grade (≤6) Gleason score (GS), 55% had GS 7 (40% of 3 + 4 and 15% of 4 + 3) and 14% had high GS (≥8) PC. The median follow-up of the cohort was 113 months. A total of 34% had a biochemical relapse, 4% developed bone metastasis and 3% of patients died from PC while 9% died of other causes. Pathological review of the TMAs confirmed the presence of tumor and benign tissue cores for > 94% of patients. Immunohistochemistry and FISH analyses, performed on a small set of specimens, showed high quality results and no biorepository-specific bias.

Conclusions: The CPCBN RP cohort is representative of real world PC disease observed in the Canadian population. The frequency of biochemical relapse and bone metastasis as events allows for a precise assessment of the prognostic value of biomarkers. This resource is available, in a step-wise manner, for researchers who intend to validate prognostic biomarkers in PC. Combining multiple biomarkers with clinical and pathologic parameters that are predictive of outcome will aid in clinical decision-making for patients treated for PC.
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http://dx.doi.org/10.1186/s12894-018-0392-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131811PMC
September 2018

Describing perspectives of health care professionals on active surveillance for the management of prostate cancer.

BMC Health Serv Res 2018 06 8;18(1):430. Epub 2018 Jun 8.

Institut du cancer de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal, 900, St Denis St, Montréal, QC, Canada.

Background: Over the last decade, active surveillance has proven to be a safe approach for patients with low-risk prostate cancer. Although active surveillance presents several advantages for both patients and the health care system, all eligible patients do not adopt this approach. Our goal was to evaluate the factors that influence physicians to recommend active surveillance and the barriers that impact adherence to this approach.

Methods: Focus groups (n = 5) were held with physicians who provided care for men with low-risk prostate cancer and had engaged in conversations with men and their families about active surveillance. The experience of health care professionals (HCPs) was captured to understand their decisions in proposing active surveillance and to reveal the barriers and facilitators that affect the adherence to this approach. A content analysis was performed on the verbatim transcripts from the sessions.

Results: Although physicians agreed that active surveillance is a suitable approach for low-risk prostate cancer patients, they were concerned about the rapidly evolving and non-standardized guidelines for patient follow-up. They pointed out the need for additional tools to appropriately identify proper patients for whom active surveillance is the best option. Urologists and radiation-oncologists were keen to collaborate with each other, but the role of general practitioner remained controversial once patients were referred to a specialist.

Conclusions: Integration of more reliable tools and/or markers in addition to more specific guidelines for patient follow-up would increase the confidence of both patients and physicians in the choice of active surveillance.
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http://dx.doi.org/10.1186/s12913-018-3273-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994022PMC
June 2018

Surveillance guidelines based on recurrence patterns for upper tract urothelial carcinoma.

Can Urol Assoc J 2018 Aug 12;12(8):243-251. Epub 2018 Apr 12.

University of British Columbia, Vancouver, BC, Canada.

Introduction: Upper tract urothelial carcinoma (UTUC) accounts for 5% of all urothelial tumours. Due to its rarity, evidence regarding postoperative surveillance is lacking. The objective of this study was to develop a post-radical nephroureterectomy (RNU) surveillance protocol based on recurrence patterns in a large, multi-institutional cohort of patients.

Methods: Retrospective clinical and pathological data were collected from 1029 patients undergoing RNU over a 15-year period (1994-2009) at 10 Canadian academic institutions. A multivariable model was used to identify prognostic clinicopathological factors, which were then used to define risk categories. Risk-based surveillance guidelines were proposed based on actual recurrence patterns.

Results: Overall, 555 (49.9%) patients developed recurrence, including 289 (25.9%) in the urothelium and 266 (23.9%) with loco-regional and distant recurrences. Based on multivariable analysis, three risk groups were identified: 1) low-risk patients with pTa-T1, pN0 disease, and no adverse histological features (high tumour grade, lymphovascular invasion [LVI], tumour multifocality); 2) intermediate-risk patients with pTa-T1, pN0 disease with one or more of the adverse histological features; and 3) high-risk patients with a ≥pT2 tumour and/or nodal involvement. Low-, intermediate-, and high-risk patients were free of urothelial recurrence at three years in 72%, 66%, and 63%, respectively, and free of regional/distant recurrence in 93%, 87%, and 62%, respectively. The risks of loco-regional and distant recurrences (p<0.0001) and time to death (p<0.0001) were significantly different between the low-, intermediate-, and high-risk patients.

Conclusions: Based on recurrence patterns in a large, multicentre patient cohort, we have proposed an evidence-based, risk-adapted post-RNU surveillance protocol.
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http://dx.doi.org/10.5489/cuaj.5377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6114151PMC
August 2018

Is Routine Renal Tumor Biopsy Associated with Lower Rates of Benign Histology following Nephrectomy for Small Renal Masses?

J Urol 2018 10 11;200(4):731-736. Epub 2018 Apr 11.

Division of Urology, Departments of Surgery, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, Ontario, Canada.

Purpose: Renal tumor biopsies have been proposed as a management alternative to avoid treatment of benign or low risk small renal masses. However, many urologists are reluctant to recommend renal tumor biopsy because they feel its result frequently will not impact management. Our primary objective was to evaluate if centers that routinely favor renal tumor biopsy have lower rates of benign histology after surgery than centers where a selective renal tumor biopsy approach is used.

Materials And Methods: This was a retrospective multicenter study of patients who underwent partial or radical nephrectomy for a lesion suspicious for localized renal cell carcinoma which measured 4 cm or less (cT1a and pT1a or pT3a) between 2013 and 2015. A logistic regression model was used to examine whether the odds of obtaining a benign tumor following surgery differed between centers that routinely favor renal tumor biopsy and centers where a selective renal tumor biopsy approach is used.

Results: A total of 542 small renal masses in 516 patients were included in study. The rate of histologically benign tumors after surgery was 11%. This rate was significantly lower at centers that routinely favor renal tumor biopsy than at centers where a selective renal tumor biopsy approach is used (5% vs 16%, p <0.001). On multivariable analysis older age, smaller tumors and centers where a selective renal tumor biopsy approach is used were significantly associated with greater odds of finding a histologically benign tumor postoperatively. Compared to centers that routinely favor renal tumor biopsy the odds of finding a benign tumor at surgery was 4 times more likely at centers where a selective renal tumor biopsy approach is used (OR 4.1, 95% CI 1.9-8.3).

Conclusions: Routine renal tumor biopsy reduces surgery for benign tumors and the potential for short-term and long-term morbidity associated with these procedures. This study suggests that routine renal tumor biopsy may be a valuable tool to decrease overtreatment of small renal masses.
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http://dx.doi.org/10.1016/j.juro.2018.04.015DOI Listing
October 2018

Prognostic and predictive clinical factors in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel.

Can Urol Assoc J 2018 Aug 6;12(8):E365-E372. Epub 2018 Apr 6.

Princess Margaret Cancer Centre, Toronto, ON, Canada.

Introduction: Cabazitaxel is one of several treatment options available for patients with metastatic castration-resistant prostate cancer who have progressed on docetaxel. Little is known about clinical factors that influence prognosis or treatment response for patients receiving cabazitaxel. Identifying prognostic and predictive factors could contribute to the optimal selection of patients for treatment after docetaxel.

Methods: A retrospective review of patients enrolled on the cabazitaxel Canadian Early Access Program (C-EAP) was performed. Clinical factors were analyzed by univariable and multivariable Cox proportional hazards and logistic regression analysis to identify independent predictors of prognosis and response.

Results: Forty-five patients from five centres in Canada were included in this study. On multivariable analysis, lower hemoglobin was associated with shorter survival. No other factors were independently associated with survival, prostate-specific antigen (PSA) response, or primary PSA progression.

Conclusions: Clinical factors predicting survival or treatment response were not identified for men with castration-resistant prostate cancer receiving cabazitaxel. Larger studies may be necessary to identify clinical factors and biomarkers that identify whether patients should or should not receive cabazitaxel.
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http://dx.doi.org/10.5489/cuaj.5108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6114156PMC
August 2018

Follow-up imaging after nephrectomy for cancer in Canada: urologists' compliance with guidelines. An observational study.

CMAJ Open 2017 Dec;5(4):E834-E841

Affiliations: McGill University and McGill University Health Centre (Dragomir, Aprikian, Tanguay), Montréal, Que; McMaster University (Kapoor), Hamilton, Ont.; Princess Margaret Cancer Centre and University of Toronto (Finelli), Toronto, Ont.; Université Laval (Pouliot), Québec, Que.; Dalhousie University and Queen Elizabeth II Health Sciences Centre (Rendon), Halifax, NS; University of British Columbia (Black), Vancouver, BC; University of Alberta (Moore), Edmonton, Alta.; University of Ottawa (Breau), Ottawa, Ont.; University of Alberta (Kawakami), Calgary, Alta.; University of Manitoba (Drachenberg), Winnipeg, Man.; University of Montréal (Lattouf), Montréal, Que.

Background: Surgical tumour removal remains the preferred treatment for most patients with renal cell carcinoma, and many medical associations have proposed guidelines for the optimal surveillance of patients following surgery. This study evaluated the adherence of Canadian urologists to the follow-up guidelines proposed by the Canadian Urological Association (CUA) in 2009.

Methods: The study cohort was identified from the Canadian Kidney Cancer Information System, a prospectively populated database from 15 academic institutions in 6 Canadian provinces: British Colombia, Alberta, Manitoba, Ontario, Quebec and Nova Scotia. A total of 1982 patients who underwent radical or partial nephrectomy for stage pT1-3N0M0 renal cancer between January 2011 and June 2016 were included in the cohort. Numbers of abdominal and chest imaging tests performed during the follow-up period were captured and compared with the 2009 CUA guidelines. The level of compliance was measured by means of weighted κ and Pearson correlation statistics. Multivariate logistic regression was used to evaluate factors associated with noncompliance (under- or overtesting) in the postoperative surveillance period.

Results: Of the 1982 patients, 1380 had stage pT1 disease, 164 had stage pT2 disease, and 438 had stage pT3 disease. There was incongruent adherence to the CUA surveillance guidelines, with a ratio of observed to recommended tests of 0.71 and 2.27 for chest and abdominal imaging, respectively. Overall, moderate correlation between observed and recommended tests was observed, with the highest value found for abdominal imaging in the pT3 group (κ = 0.59 [95% confidence interval 0.52-0.66]). Patients who underwent radical nephrectomy and those who presented with a higher stage of the disease were less likely to receive fewer chest imaging tests than recommended, and those with stage pT2 disease, those with stage pT3 disease, those with conventional clear cell renal cell carcinoma and those with a low-risk histologic type had an increased risk of undertesting.

Interpretation: In the 6 Canadian provinces, there are large differences between guidelines and clinical practice in imaging surveillance after nephrectomy for renal cell carcinoma. Better adherence to clinical guidelines could improve optimization of health care services.
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http://dx.doi.org/10.9778/cmajo.20170005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741415PMC
December 2017

Canadian Men's perspectives about active surveillance in prostate cancer: need for guidance and resources.

BMC Urol 2017 Oct 27;17(1):98. Epub 2017 Oct 27.

Institut du cancer de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal, 900 St Denis St, Montreal, QC, Canada.

Background: In prostate cancer, men diagnosed with low risk disease may be monitored through an active surveillance. This research explored the perspectives of men with prostate cancer regarding their decision-making process for active surveillance to identify factors that influence their decision and assist health professionals in having conversations about this option.

Methods: Focus group interviews (n = 7) were held in several Canadian cities with men (N = 52) diagnosed with prostate cancer and eligible for active surveillance. The men's viewpoints were captured regarding their understanding of active surveillance, the factors that influenced their decision, and their experience with the approach. A content and theme analysis was performed on the verbatim transcripts from the sessions.

Results: Patients described their concerns of living with their disease without intervention, but were reassured by the close monitoring under AS while avoiding harmful side effects associated with treatments. Conversations with their doctor and how AS was described were cited as key influences in their decision, in addition to availability of information on treatment options, distrust in the health system, personality, experiences and opinions of others, and personal perspectives on quality of life.

Conclusions: Men require a thorough explanation on AS as a safe and valid option, as well as guidance towards supportive resources in their decision-making.
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http://dx.doi.org/10.1186/s12894-017-0290-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658971PMC
October 2017

Development and Implementation of a Continuing Medical Education Program in Canada: Knowledge Translation for Renal Cell Carcinoma (KT4RCC).

J Cancer Educ 2019 02;34(1):14-18

Division of Urology, Department of Surgery, The Ottawa Hospital, 501 Smyth Rd, Ottawa, ON, K1H 8L6, Canada.

An in-person multidisciplinary continuing medical education (CME) program was designed to address previously identified knowledge gaps regarding quality indicators of care in kidney cancer. The objective of this study was to develop a CME program and determine if the program was effective for improving participant knowledge. CME programs for clinicians were delivered by local experts (uro-oncologist and medical oncologist) in four Canadian cities. Participants completed knowledge assessment tests pre-CME, immediately post-CME, and 3-month post-CME. Test questions were related to topics covered in the CME program including prognostic factors for advanced disease, surgery for advanced disease, indications for hereditary screening, systemic therapy, and management of small renal masses. Fifty-two participants attended the CME program and completed the pre- and immediate post-CME tests. Participants attended in Ottawa (14; 27%), Toronto (13; 25%), Québec City (18; 35%), and Montréal (7; 13%) and were staff urologists (21; 40%), staff medical oncologists (9; 17%), fellows (5; 10%), residents (16; 31%), and oncology nurses (1; 2%). The mean pre-CME test score was 61% and the mean post-CME test score was 70% (p = 0.003). Twenty-one participants (40%) completed the 3-month post-CME test. Of those that completed the post-test, scores remained 10% higher than the pre-test (p value 0.01). Variability in test scores was observed across sites and between French and English test versions. Urologists had the largest specialty-specific increase in knowledge at 13.8% (SD 24.2, p value 0.02). The kidney cancer CME program was moderately effective in improving provider knowledge regarding quality indicators of kidney cancer care. These findings support continued use of this CME program at other sites.
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http://dx.doi.org/10.1007/s13187-017-1259-7DOI Listing
February 2019

Error reporting from the da Vinci surgical system in robotic surgery: A Canadian multispecialty experience at a single academic centre.

Can Urol Assoc J 2017 May 9;11(5):E197-E202. Epub 2017 May 9.

Division of Urology, University of Montreal Hospital Centre (CHUM), Montreal, QC, Canada.

Introduction: The goal of the study is to evaluate and report on the third-generation da Vinci surgical (Si) system malfunctions.

Methods: A total of 1228 robotic surgeries were performed between January 2012 and December 2015 at our academic centre. All cases were performed by using a single, dual console, four-arm, da Vinci Si robot system. The three specialties included urology, gynecology, and thoracic surgery. Studied outcomes included the robotic surgical error types, immediate consequences, and operative side effects. Error rate trend with time was also examined.

Results: Overall robotic malfunctions were documented on the da Vinci Si systems event log in 4.97% (61/1228) of the cases. The most common error was related to pressure sensors in the robotic arms indicating out of limit output. This recoverable fault was noted in 2.04% (25/1228) of cases. Other errors included unrecoverable electronic communication-related in 1.06% (13/1228) of cases, failed encoder error in 0.57% (7/1228), illuminator-related in 0.33% (4/1228), faulty switch in 0.24% (3/1228), battery-related failures in 0.24% (3/1228), and software/hardware error in 0.08% (1/1228) of cases. Surgical delay was reported only in one patient. No conversion to either open or laparoscopic occurred secondary to robotic malfunctions. In 2015, the incidence of robotic error rose to 1.71% (21/1228) from 0.81% (10/1228) in 2014.

Conclusions: Robotic malfunction is not infrequent in the current era of robotic surgery in various surgical subspecialties, but rarely consequential. Their seldom occurrence does not seem to affect patient safety or surgical outcome.
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http://dx.doi.org/10.5489/cuaj.4116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5426941PMC
May 2017

Heterogeneous Nuclear Ribonucleoprotein F Stimulates Sirtuin-1 Gene Expression and Attenuates Nephropathy Progression in Diabetic Mice.

Diabetes 2017 07 19;66(7):1964-1978. Epub 2017 Apr 19.

Centre de recherche, Centre hospitalier de l'Université de Montréal (CRCHUM) and Département de médecine, Université de Montréal, Montreal, QC, Canada

We investigated the mechanism of heterogeneous nuclear ribonucleoprotein F (hnRNP F) renoprotective action in a type 2 diabetes (T2D) mouse model (/). Immortalized rat renal proximal tubular cells (IRPTCs) and kidneys from humans with T2D were also studied. The / mice developed hyperglycemia, oxidative stress, and nephropathy at age 20 weeks compared with their / littermates. These abnormalities, with the exception of hyperglycemia, were attenuated in /-transgenic (Tg) mice specifically overexpressing hnRNP F in their RPTCs. Sirtuin-1, Foxo3α, and catalase expression were significantly decreased in RPTCs from / mice and normalized in /-Tg mice. In vitro, hnRNP F overexpression stimulated Sirtuin-1 and Foxo3α with downregulation of acetylated p53 expression and prevented downregulation of Sirtuin-1 and Foxo3α expression in IRPTCs by high glucose plus palmitate. Transfection of small interfering RNA prevented hnRNP F stimulation of Foxo3α and downregulation of acetylated p53 expression. hnRNP F stimulated transcription via -responsive element in the promoter. Human T2D kidneys exhibited more RPTC apoptosis and lower expression of hnRNP F, SIRTUIN-1, and FOXO3α than nondiabetic kidneys. Our results demonstrate that hnRNP F protects kidneys against oxidative stress and nephropathy via stimulation of expression and signaling in diabetes.
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http://dx.doi.org/10.2337/db16-1588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482081PMC
July 2017